The long-term objective of this study is to compare the effects of defined immune system mediators on central nervous system function in normal animals and in animals given opioid drugs. Specifically, interleukin-1, tumor necrosis factor and interferon-gamma will be tested for their ability to alter pain perception and thermoregulation (including body temperature, whole-body heat loss and basal metabolism) when these substances are given alone or in combination with opioids. Interaction between the opioids and the immune mediators will be assessed by measuring inhibitory, additive or synergistic effects in these physiologic tests. Based on preliminary studies in which we have found one instance of interaction and one instance of non-interaction between the temperature effects of interleukin-1 and two doses of morphine, we expect to find further interaction among permutative combinations of various opioids with various immune mediators. Where interactive effects are discovered, selective opioid with various immune mediators. Where interactive effects are discovered, selective opioid agonists and antagonists will be used to further investigate the interaction(s). An increasing body of literature points to an intimate interaction between the nervous and immune systems. However, there are few studies in which there has been a systematic exploration of the drugs of abuse. The proposed studies may provide new insights into the interplay between products of the activated immune system during infection and the capacity of infected individuals to respond to opioids used therapeutically or as drugs of abuse.